Thrombosis and Haemostasis

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ISSN / EISSN : 0340-6245 / 2567-689X
Published by: Thieme Medical Publishers (10.1055)
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Maria A. de Winter, Jannick A. N. Dorresteijn, Walter Ageno, Cihan Ay, Jan Beyer-Westendorf, Michiel Coppens, , Farès Moustafa, , , et al.
Thrombosis and Haemostasis; https://doi.org/10.1055/s-0041-1735251

Abstract:
Background Bleeding risk is highly relevant for treatment decisions in cancer-associated thrombosis (CAT). Several risk scores exist, but have never been validated in patients with CAT and are not recommended for practice. Objectives To compare methods of estimating clinically relevant (major and clinically relevant nonmajor) bleeding risk in patients with CAT: (1) existing risk scores for bleeding in venous thromboembolism, (2) pragmatic classification based on cancer type, and (3) new prediction model. Methods In a posthoc analysis of the Hokusai VTE Cancer study, a randomized trial comparing edoxaban with dalteparin for treatment of CAT, seven bleeding risk scores were externally validated (ACCP-VTE, HAS-BLED, Hokusai, Kuijer, Martinez, RIETE, and VTE-BLEED). The predictive performance of these scores was compared with a pragmatic classification based on cancer type (gastrointestinal; genitourinary; other) and a newly derived competing risk-adjusted prediction model based on clinical predictors for clinically relevant bleeding within 6 months after CAT diagnosis with nonbleeding-related mortality as the competing event (“CAT-BLEED”). Results Data of 1,046 patients (149 events) were analyzed. Predictive performance of existing risk scores was poor to moderate (C-statistics: 0.50–0.57; poor calibration). Internal validation of the pragmatic classification and “CAT-BLEED” showed moderate performance (respective C-statistics: 0.61; 95% confidence interval [CI]: 0.56–0.66, and 0.63; 95% CI 0.58–0.68; good calibration). Conclusion Existing risk scores for bleeding perform poorly after CAT. Pragmatic classification based on cancer type provides marginally better estimates of clinically relevant bleeding risk. Further improvement may be achieved with “CAT-BLEED,” but this requires external validation in practice-based settings and with other DOACs and its clinical usefulness is yet to be demonstrated.
, Giancarlo Agnelli, Cihan Ay, , Cecilia Becattini, Marc Carrier, Céline Chapelle, Alexander T Cohen, Philippe Girard, Menno V Huisman, et al.
Thrombosis and Haemostasis; https://doi.org/10.1055/a-1647-9896

Abstract:
Cancer-associated thrombosis (CAT) is associated with a high risk of recurrent venous thromboembolic events (VTE) that require extended anticoagulation in patients with active cancer, putting them at risk of bleeding.The aim of the API-CAT study (NCT03692065) is to assess whether a reduced-dose regimen of apixaban (2.5 mg twice daily [bid]) is non-inferior to a full-dose regimen of apixaban (5 mg bid) for the prevention of recurrent VTE in patients with active cancer who have completed ≥6 months of anticoagulant therapy for a documented index event of proximal deep-vein thrombosis and/or pulmonary embolism.APICAT is an international, randomized, parallel-group, double-blind, non-inferiority trial with blinded adjudication of outcome events. Consecutive patients are randomized to receive apixaban 2.5 mg or 5 mg bid for 12 months. The primary efficacy outcome is a composite of recurrent symptomatic or incidental VTE during the treatment period. The principal safety endpoint is clinically relevant bleeding, defined as a composite of major bleeding or non-major clinically relevant bleeding. Assuming a 12-month incidence of the primary outcome of 4% with apixaban and an upper limit of the 2-sided 95% confidence interval of the hazard ratio <2.0, 1722 patients will be randomized,assuming an up to 10% loss in total patient-years (β = 80%; α 1-sided = 0.025). This trialhas the potential to demonstrate that a regimen of extended treatment for patients with CAT beyond an initial 6 months, with a reduced apixaban dose,has an acceptable risk of recurrent VTE recurrence and decreases the risk of bleeding.
, Andrés Muñoz, Laura Franco, , Benjamin Brenner, Jean M. Connors, Gualberto Gussoni, Eva N. Hamulyak, Catherine Lambert, Maria Rosales Suero, et al.
Thrombosis and Haemostasis; https://doi.org/10.1055/s-0041-1735194

Abstract:
Efficacy and safety of anticoagulant treatment for venous thromboembolism (VTE) may vary in patients with different cancer sites. We evaluated the rates of VTE recurrence and major bleeding and the relative efficacy and safety of 6-month treatment with oral apixaban or subcutaneous dalteparin in patients with different cancer sites randomized in the Caravaggio study. Primary cancer was located at gastrointestinal sites in 375 patients (32.5%), lung in 200 (17.3%), breast in 155 (13.4%), genitourinary sites in 139 (12%), gynecological sites in 119 (10.3%), and was hematological in 85 patients (7.4%). Rates of VTE recurrence were 10.9% in patients with gynecological, 8.8% with gastrointestinal, 6.5% with genitourinary, and 5.5% with lung cancer with lower rates in the other sites of cancer. Rates of major bleeding were 7.2% in patients with genitourinary and 4.8% with gastrointestinal cancer, with lower rates in patients with other sites of cancer. The observed absolute risk difference in VTE recurrence in favor of apixaban was 11.9% in patients with gynecological, 5.5% with lung, 3.7% with genitourinary cancer, and 0.6% with gastrointestinal cancer. None of the risk differences was statistically significant. The rates of major bleeding in patients treated with apixaban or dalteparin was similar across patients with different cancer sites. In conclusion, recurrences appear to be more common in patients with gastrointestinal and gynecological cancer and major bleedings in patients with genitourinary and gastrointestinal cancer. Oral apixaban is a valid oral alternative to subcutaneous dalteparin for the treatment of a large spectrum of patients with cancer-associated VTE.
, Heather Hogan, Ruth Morrison, John Fanikos, Umberto Campia, Briana Barns, Mariana Pfeferman, Julia Snyder, Candrika Khairani, Samuel Z Goldhaber, et al.
Thrombosis and Haemostasis; https://doi.org/10.1055/a-1646-2244

Abstract:
Patients with acute venous thromboembolism (VTE) in the setting of transient provoking factors are typically treated with short-term anticoagulation. However, the risk of recurrence may be increased in the presence of enduring risk factors. In such patients, the optimal duration of treatment remains uncertain. HI-PRO is a single-center, double-blind randomized trial. Patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) following a major provoking factor, including major surgery or major trauma, who completed at least 3 months of standard-dose therapeutic anticoagulation and have at least one enduring risk factor (such as obesity or heart failure), will be considered for inclusion. Patients will be randomized to apixaban 2.5 mg twice daily or placebo for 12 months. The primary efficacy outcome will be symptomatic recurrent VTE –a composite of DVT and/or PE at 12 months after randomization. Secondary efficacy outcomes include a composite of death due to cardiovascular causes, nonfatal myocardial infarction, stroke or systemic embolism, major adverse limb events, or coronary or peripheral ischemia requiring revascularization at 12 months, and individual components of these outcomes. The primary safety outcome is major bleeding according to the International Society on Thrombosis and Haemostasis definition. The study plans to enroll 600 patients (300 per arm) to have 80% power for detecting a 75% relative risk reduction in the primary outcome. Active recruitment began in March 2021. HI-PRO will provide clinically meaningful data on whether patients with provoked VTE and enduring risk factors have fewer adverse clinical outcomes if prescribed low-intensity extended duration anticoagulation.
, Mira Naamad, Dafna Frydman, Michael R. Freund, Tama Dinur, Majdolen Istaiti, Michal Becker-Cohen, Roni Falk, Eti Broide, Alan D. Michelson, et al.
Thrombosis and Haemostasis; https://doi.org/10.1055/a-1642-4206

Abstract:
Patients with Gaucher disease (GD) are at increased risk of bleeding and have varying degrees of thrombocytopenia, making the analysis of platelet function difficult. This study aimed to provide a clinically relevant quantitative assessment of platelet function and determine its relationship with bleeding and GD-related data. Methods: Unstimulated and stimulated platelet function was measured by whole blood flow cytometry of platelet surface activated αIIbβ3 integrin (detected with monoclonal antibody PAC1), P-selectin (CD62P), and lysosomal-associated membrane protein (LAMP3/CD63) in 149 GD patients. Results: GD patients had a higher level of unstimulated CD63 expression than healthy subjects, which was mildly correlated with glucosylsphingosine (lyso-Gb1) levels (r 0.17, p-value 0.042). Splenectomized GD patients had a higher level of unstimulated αIIbβ3 integrin and P-selectin expression. Reduced platelet reactivity (-2 SD of reference range) was found in 79 (53%, 95% CI 44%-61%) patients, of whom 10 (6.7%, 95% CI 3.3%-12%) had more severe platelet dysfunction. In a multivariate model, only lyso-Gb1 levels were associated with the more severe platelet dysfunction. Fifty-four (49%) of 128 adult patients who completed the bleeding tendency questionnaire reported positive bleeding history. In a multivariate logistic model, older age (OR (95% CI), 1.05 (1.01-1.1)) and low P-selectin reactivity (OR (95% CI), 2.03 (1.25-3.35)) were associated with more than one bleeding manifestation. Conclusion: Flow cytometry enables the study of platelet function in thrombocytopenic GD patients. A platelet degranulation defect, but not αIIbβ3 integrin activation defect, is associated with clinical bleeding. In vivo increased CD63 expression may be related to GD-related inflammation.
, Cihan Ay, Manuela Carvalho, Roseline D'Oiron, Philippe De Moerloose, Gerard Dolan, , Cedric Hermans, Pål Andre Holme, Olga Katsarou, et al.
Thrombosis and Haemostasis; https://doi.org/10.1055/a-1642-4067

Abstract:
Introduction: A second peak of inhibitors has been reported in patients with severe haemophilia A (HA) aged >50 years in the UK.1 The reason for this suggested breakdown of tolerance in the ageing population is unclear, as is the potential impact of regular exposure to the deficient factor by prophylaxis at higher age. No data on haemophilia B (HB) has ever been reported. Aim: The ADVANCE Working Group investigated the incidence of late-onset inhibitors and the use of prophylaxis in patients with HA and HB aged ≥40 years. Methods: A retrospective, observational, cohort, survey-based study of all patients aged ≥40 years with HA or HB treated at an ADVANCE HTC. Results: Information on 3,095 people aged ≥40 years with HA or HB was collected. Of the 2,562 patients with severe HA, the majority (73% across all age groups) received prophylaxis. In patients with severe HA, the inhibitor incidence per 1,000 treatment years was 2.37 (age 40–49), 1.25 (age 50–59) and 1.45 (age 60+). Overall, the inhibitor incidence was greatest in those with moderate HA (5.77 (age 40–49), 6.59 (age 50–59) and 4.69 (age 60+) and the majority of inhibitor cases were preceded by a potential immune system challenge. No inhibitors in patients with haemophilia B were reported. Conclusion: Our data do not identify a second peak of inhibitor development in older patients with haemophilia. Prophylaxis may be beneficial in older patients with severe, and possibly moderate HA, to retain a tolerant state at higher age.
, Haocheng Lu, Jinjian Sun, Guizhen Zhao, Huilun Wang, Yanhong Guo, Daniel Eitzman, Y Eugene Chen, Yanbo Fan,
Thrombosis and Haemostasis; https://doi.org/10.1055/s-0041-1735191

Abstract:
Krüppel-like factors (KLFs) play essential roles in multiple biological functions, including maintaining vascular homeostasis. KLF11, a causative gene for maturity-onset diabetes of the young type 7, inhibits endothelial activation and protects against stroke. However, the role of KLF11 in venous thrombosis remains to be explored. Utilizing stasis-induced murine deep vein thrombosis (DVT) model and cultured endothelial cells (ECs), we identified an increase of KLF11 expression under prothrombotic conditions both in vivo and in vitro. The expression change of thrombosis-related genes was determined by utilizing gain- and loss-of-function approaches to alter KLF11 expression in ECs. Among these genes, KLF11 significantly downregulated tumor necrosis factor-α (TNF-α)-induced tissue factor (TF) gene transcription. Using reporter gene assay, chromatin immunoprecipitation assay, and co-immunoprecipitation, we revealed that KLF11 could reduce TNF-α-induced binding of early growth response 1 (EGR1) to TF gene promoter in ECs. In addition, we demonstrated that conventional Klf11 knockout mice were more susceptible to developing stasis-induced DVT. These results suggest that under prothrombotic conditions, KLF11 downregulates TF gene transcription via inhibition of EGR1 in ECs. In conclusion, KLF11 protects against venous thrombosis, constituting a potential molecular target for treating thrombosis.
, Stefan Handtke
Thrombosis and Haemostasis; https://doi.org/10.1055/s-0041-1735190

Abstract:
High-Dose Epinephrine Enhances Platelet Aggregation at the Expense of Procoagulant Activity Epinephrine (adrenaline) is a hormone synthesized by the adrenal gland medulla and by neurons. It is released following physical activity, mental stress, or other conditions associated with sympathoadrenal activation.[1] Platelets exhibit α2A adrenergic receptors making them susceptible to systemic epinephrine release. In this context, epinephrine can influence platelet reactivity under systemic stress. Epinephrine has a rather indirect mode of action by amplifying the response to other agonists.[2] In this issue of Thrombosis and Haemostasis, Aliotta et al[3] investigated the additional impact of epinephrine on procoagulant collagen and thrombin coated (COAT) platelets. COAT platelets are formed after co-stimulation of protease-activated receptors and glycoprotein VI, e.g., with thrombin and convulxin, respectively. COAT platelet formation is associated with phosphatidylserine (PS) exposure and a sustained cytosolic Ca2+ increase and affects a higher proportion of large platelets.[4] The authors confirm that epinephrine stimulation alone does not affect free cytosolic Ca2+ and elegantly show that it dose dependently reduces free cytosolic Ca2+ of thrombin + convulxin stimulated platelets. This decreases the proportion of PS-positive COAT platelets and increases the proportion of PAC-1-binding aggregatory platelets. Thus, very high doses of 1,000 µM epinephrine switch the platelet response from a procoagulant phenotype toward aggregation. Albeit such high epinephrine concentrations appear less likely to occur in vivo, Aliotta and colleagues discuss that platelets respond to a 15- to 55-fold lower epinephrine concentration in vivo. Extrapolating their data, such a switch could appear at doses of 6 µM, coming near to systemic concentrations achieved after epinephrine injection. Further, it is unknown which concentrations of epinephrine appear in the microenvironment around vascular injuries, where platelets begin to act. This deserves future investigations. Meanwhile, it is a rational hypothesis that epinephrine modulates procoagulant COAT and pro-aggregatory platelet formation when the organism is alarmed or when patients receive high doses of catecholamines. Received: 23 July 2021Accepted: 26 July 2021Publication Date:24 August 2021 (online) © 2021. Thieme. All rights reserved. Georg Thieme Verlag KGRüdigerstraße 14, 70469 Stuttgart, Germany
Thrombosis and Haemostasis; https://doi.org/10.1055/s-0041-1735189

Abstract:
Risk of Ischemic Stroke in Asymptomatic Atrial Fibrillation Incidentally Detected in Primary Care Compared with Other Clinical Presentations There has been much advocacy for the implementation of screening strategies for asymptomatic atrial fibrillation (AF),[1] given the high health care burden associated with this common arrhythmia.[2] Importantly, AF can occur asymptomatically in up to 40% of the cases, even though no profound differences were reported between symptomatic and asymptomatic AF patients in terms of risk for adverse outcomes.[3] [4] Based on this evidence, implementing screening strategies to effectively identify unknown AF patients has highlighted how structured screening strategies are effective in identifying a higher number of high-risk AF patients needing the prescription of oral anticoagulants (OACs), and that using such strategies to increase OAC can be cost-effective.[5] [6] [7] Notwithstanding this, most of the studies reported thus far have only focused on the diagnostic yield related to the screening procedure and were not designed or powered to identify a significant clinical benefit in reducing adverse events in screened patients compared with those incidentally diagnosed with AF.[1] On the basis of this lack of evidence, in 2018 the United States Preventive Services Task Force (USPSTF) released a statement which still did not recommend the use of large-scale systematic screening strategies to identify AF patients.[8] [9] In this issue of Thrombosis and Haemostasis, Wallenhorst and colleagues present an interesting and topical analysis[10] derived from the United Kingdom Clinical Practice Research Datalink, linked to the Hospital Episodes Statistics and the Office for National Statistics to gather information regarding hospital admissions and mortality data. In this analysis using International Classification of Diseases-10th Revision codes, the authors analyzed 22,035 adult (18–84 years old) subjects with incident AF from January 1, 2001 to October 31, 2009 categorized according to the mode of AF detection. Hence, the patients were divided as follows: (1) asymptomatic incidentally detected ambulatory AF (AA-AF) [N = 5,409, 24.5%)]; (2) symptomatic ambulatory AF (SA-AF) [N = 5,913, 26.8%]; (3) AF as primary hospital discharge diagnosis (PH-AF) [N = 4,989, 22.6%); (4) AF as nonprimary hospital discharge diagnosis (Non-PH-AF) [N = 26.0%]. The study cohort was then analyzed and compared with 23,605 non-AF matched patients, regarding the occurrence of stroke and all-cause death during long-term follow-up. At baseline, AA-AF patients were found to be less affected by comorbidities, with an overall low thromboembolic risk, similarly to non-AF patients. Conversely, the non-PH-AF group showed the highest burden of comorbidities and the highest level of thromboembolic risk. SA-AF and PH-AF patients showed a mixed clinical profile being both moderately comorbid, but with PH-AF ones being younger and with the lowest thromboembolic risk. Over a 3-year follow-up, while the non-AF group was associated to lower risk of stroke occurrence, in a fully adjusted competitive risk analysis compared with the AA-AF group, all the other three groups (SA-AF, PH-AF, and Non-PH-AF) reported no differences in the association with stroke events, as compared with the asymptomatic patients.[10] Similar results were found when restricting the observation to high-risk patients only (males with CHA2DS2-VASc ≥2 and females with CHA2DS2-VASc ≥3). Non-AF subjects were associated with a lower risk and the SA-AF and PH-AF ones showed no difference in association with all-cause death; however, non-PH-AF patients were associated with a higher risk of all-cause death compared with asymptomatic patients. Notably, the rate of OAC prescription was generally low (∼29%), with no differences between low- and high-risk patients and both AA-AF and SA-AF having the same OAC prevalence, while non-PH-AF subjects were markedly less treated with OAC (∼20%). This article allows us to highlight several important considerations regarding the modern management of AF patients. First, even in an unselected real-world cohort of subjects with first diagnosed AF, the proportion of patients with completely asymptomatic AF, which were only incidentally diagnosed, remains quite consistent, being around one-quarter of the entire study cohort. Even though those patients appeared to be slightly less burdened with comorbidities, they still have an important thromboembolic risk with more than 70% with a CHA2DS2-VASc score ≥2. Indeed, stroke risk changes with aging and incident comorbidities[11] [12] and the burden of symptoms does not necessarily influence the risk of outcomes, even in those who never have been symptomatic[4]; hence, asymptomatic AF patients should not be less intensively treated in comparison with symptomatic subjects.[3] Second, no differences in the risks of ischemic stroke between asymptomatic presentation of AF and other presentations have important clinical correlates regarding the application of opportunistic and/or systematic screening procedures in the general population. Indeed, those 5,409 asymptomatic patients who were found to be in AF were only accidentally diagnosed, mimicking what could be obtained by using an opportunistic screening applied to the entire population. If such patients had not been found in AF, none of them could have been prescribed with OAC and then an even larger number of strokes would have been recorded. In the 2020 European Society of Cardiology (ESC) clinical guidelines, the need for screening has been strongly emphasized.[13] Notwithstanding this, the ESC guidelines still recommend the use of opportunistic screening only in patients age ≥65 years, even though with a “B” level of evidence, while the use of systematic screening is suggested to be considered in subjects ≥75 years or with a high burden of stroke risk factors, again...
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